Men With ACPA-Negative Early RA More Likely to Achieve Remission Than Women, Study Suggests

According to the authors, sex-based differences may be a cause of higher rheumatoid arthritis (RA) disease activity.

Among patients with rheumatoid arthritis (RA), male sex was linked to better clinical outcomes in early RA without the presence of anti–citrullinated peptide antibody (ACPA), but there was no association with outcomes in ACPA-positive early RA, a study published in The Journal of Rheumatology found.

It showed a particularly low proportion of female patients with ACPA-negative early RA who achieved remission, suggesting the disease is more difficult to successfully treat in women than men.

The Swedish study consisted of 2 inception cohorts of 426 total consecutive patients with early RA, defined as less than 12 months since symptom onset. Of the 426 patients, 233 were included in cohort 1, and the other 283 were in cohort 2. Most (304 [71.4%]) patients were female.

In cohort 1, 225 patients had Disease Activity Score (DAS28) data available at baseline. Of these patients, 130 were ACPA-positive and 95 were ACPA-negative, and both groups had more than double the amount of women than men.

Only 201 patients from cohort 2 had data on DAS28 at baseline. This subgroup consisted of 136 ACPA-positive and 65 ACPA-negative patients with RA. While the ratio of women to men was a bit closer for the ACPA-negative group—41 women and 24 men—there was a bigger gap in the ratio in the ACPA-positive group, with 105 women and 31 men. For both cohorts, disease characteristics at baseline were similar between groups based on sex and ACPA status.

Of the total 426 patients with early RA, 27% of women and 24% of men with ACPA-positive RA achieved DAS28 remission at 12 months. For the ACPA-negative group specifically, DAS28 remission was achieved by 16% of women and 49% of men.

In this group, men had higher odds of achieving remission (pooled adjusted odds ratio [OR], 4.79; 95% CI, 1.97-11.6). However, this was not the case in the ACPA-positive group (pooled adjusted OR, 1.06; 95 % CI, 0.49-2.30).

RA incidence is higher in female patients compared with male patients, making this lower chance of remission for women with early RA concerning.

“One possible explanation for our findings is that disease activity in females with ACPA-negative RA was partly driven by non-inflammatory joint pain,” the study authors explained. “Indeed, fibromyalgia, which is often associated with RA, as well as other widespread musculoskeletal pain syndromes are more prevalent in females and ACPA negativity has been reported to be a risk factor for fibromyalgia diagnosis in patients with RA.”

They also noted that immunosuppressive treatment does not have an effect on noninflammatory pain. Additionally, erythrocyte sedimentation rates—used to measure ACPAs in this study—are generally higher in women, which is likely a reason for the differences in DAS28 based on sex.

“Therefore, the higher disease activity in female patients may not represent a truly active inflammation, but rather a misclassification of disease activity,” the authors said.

The association between female sex and worse ACPA-negative early RA could potentially be explained by the effect of sex hormones on the pathophysiology of synovitis in RA. According to the authors, however, if that were the sole reason, the results from other similar studies would be more consistent. It would also not explain why sex was a clear negative prognostic factor specifically in ACPA-negative patients in this study.

Because this was the first study to specifically evaluate the association between sex and both ACPA-positive and ACPA-negative early RA outcomes, the authors said further research is needed before these findings can be generalized.

Cagnotto G, Jacobsson THL, Rydell E, Eberhard A, Compagno M, Turesson C. Male sex predicts a favorable outcome in early ACPA-negative rheumatoid arthritis: data from an observational study. J Rheumatol. Published online May 2, 2022. doi:10.3899/jrheum.211199

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